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WO2016003383A1 - Utilisation de l'extrait obtenu à partir de feuilles d'olive noire dans le traitement du glioblastome - Google Patents

Utilisation de l'extrait obtenu à partir de feuilles d'olive noire dans le traitement du glioblastome Download PDF

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Publication number
WO2016003383A1
WO2016003383A1 PCT/TR2015/050023 TR2015050023W WO2016003383A1 WO 2016003383 A1 WO2016003383 A1 WO 2016003383A1 TR 2015050023 W TR2015050023 W TR 2015050023W WO 2016003383 A1 WO2016003383 A1 WO 2016003383A1
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WIPO (PCT)
Prior art keywords
treatment
ole
glioblastoma
cancer stem
gbm
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Ceased
Application number
PCT/TR2015/050023
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English (en)
Inventor
Berrin TUNCA
Hulusi MALYER
Gülçin TEZCAN
Ünal EGELİ
Gülşah ÇEÇENER
Gülendam TÜMEN
Ahmet BEKAR
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Individual
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Individual
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Publication of WO2016003383A1 publication Critical patent/WO2016003383A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Present invention relates to the use of the extract of the leaves of Olea europaea (OLE) in the treatment of Glioblastoma (GBM) tumors which are characterized by cancer stem cells positivity.
  • OAE Olea europaea
  • Present invention especially relates to the activity of OLE on the tumor tissues detected to contain cancer stem cell among the GBM tumor tissues obtained from the surgery of the patients bearing different clinical properties.
  • GBM Glioblastoma
  • Glioblastoma Multiforme is the most common primer malign brain tumor among all brain tumors. This tumor is a malignant tumor, a cancer, deriving from the glial supportive tissues in star shape found in the brain, in other words from the astrocytes.
  • GBM Glioblastoma
  • TMZ Temozolomide
  • MGMT gene expression 06-methyl guanine-DNA methyl transferase
  • TMZ has been commonly used nowadays in the treatment of patients with GBM.
  • PCT applications encountered throughout the literature search is WO2013086308 (A1 ).
  • Said invention relates to use of TMS in the treatment of brain cancer.
  • US2012040914 A1 .
  • Said invention relates to the use of TMZ in the treatment of Glioblastoma.
  • TMZ shows differences according the MGMT gene expression of the patient.
  • combination therapy of TMZ with radiotherapy has major cytotoxic effects for the patient. Even if the treatment methods having such cytotoxic effects are effective in eliminating the tumor to a great extent, they may give rise to negative side effects for the patient.
  • Recent studies show that the patients, who are specified to contain cancer stem cells in their tumors, are likely to be much less responsive to the TMZ treatment.
  • JP2008273938 A
  • the invention relates to the use of olive leaves in the types of cancers such as the gastric cancer, colon cancer.
  • Another of these patent applications is CN101607068 (A1 ).
  • Said invention relates to use of olein in the treatment of liver cancer.
  • Present invention relates to the use of OLE in the treatment of cancer stem cells which meets the above mentioned requirements, eliminates the drawbacks and brings in further advantages.
  • Aim of the present invention is especially the activity of OLE on the tumorous tissues detected to contain cancer stem cell among the GBM tumorous tissues obtained from the surgery of the patients bearing different clinical properties.
  • An object of the invention is, thanks to its activity on cancer stem cells, to contribute in generating supportive protocols in the treatment of patients with GBM resisting against medicaments, in order to reduce the resistance against chemotherapeutic agents.
  • a similar object of the invention is to enhance the quality of life of the patient by reducing the possible side effects, owing to the fact that the OLE has a lower cytotoxic effect on normal cells of the patient and that it allows lower doses of TMZ to be used, which otherwise would have a high cytotoxic effect.
  • Olea europaea is used in cancer stem cells positive Glioblastoma tumors that are treated with temozolomide.
  • Figure 2 is the designation of the positiveness of CD133 and Nestin which are precursors of cancer stem cells via flow cytometry technique.
  • the invention relates to the antitumoral activity of the olive ⁇ Olea europaea) on the cancer stem cell positive Glioblastoma tumors treated with temozolomode (TMZ).
  • ethanol of the ethanol extract is turned into an extract powder by being evaporated at low pressure and temperature not exceeding 55 ⁇ in a Spray Dryer system,
  • Figure 1 shows the isolation of cancer stem cells from GBM tumors.
  • a part of the Glioblastoma tumors obtained from the patients via surgical intervention was sent to the Medical Biology AD Cell Culture Laboratories in PBS containing 5% antibiotics.
  • tissue samples were divided into small particles in the order of a pinhole with the aid of scalpel and forceps and transferred in to cell culture plates of 25cm 2 .
  • Cells, after being supplied with the growth medium are cultured without being displaced for 7 days.
  • CD133+ cells that were adhered to the surface of the culture plates belonging to the early stage passages of the cells separated via magnetic nanoparticles, were picked from the surface by 0.25% trypsin-EDTA. And they were suspended according to the kit procedure. Then the cells were treated with fluoroscein isothiocynate (FITC) specific to CD133 and Nestinl , phycoerythrin (PE)-conjugate monoclonal antibodies and suitable isotype controls. In order to clear the possible artifacts, washing was performed with PBS containing 0.1 % sodium azide and cell suspension was scanned by FACS Calibur Flow Cytometry (BD Sciences). Analysis of obtained data were performed by BD CellQuestTM software.
  • FITC fluoroscein isothiocynate
  • PE phycoerythrin
  • tissues the amount of the expression of the cancer stem cell precursors of which are at least 2 times higher compared to non-tumorous tissues are considered to be cancer stem cell positive.
  • RNA isolation kit specific to cell culture isolation of the RNA from the CD133+ cells obtained and reproduced from primer tumors was performed by mRNA isolation kit specific to cell culture. Quantification and qualification controls of the RNAs were performed by nanodrop.
  • cDNA complementary DNA
  • final RNA concentration was adjusted at least to 1-5 ⁇ g.
  • cDNA synthesis was performed from the RNAs by using Transcriptor First Strand cDNA Synthesis Kit. From obtained cDNAs, by using specific primers belonging to Vimentin, Integrin, CD44 and OCT-4 genes which are cancer stem cell markers and primers specific to B-actin gene as control, aimed levels of mRNA expression was determined. Suitable PCR mixture prepared for the expression was reproduced by using LC 480 Real Time device according to PCR protocol specific to primers. Changes in the mRNA expressions were relatively determined by performing ⁇ method for data analysis.
  • OLE is effective on the cancer stem cell positive GBM tumors.
  • OLE of the present invention shows cytotoxic effect on GBM stem cells.
  • OLE shows synergistic effect with TMZ on GBM stem cells.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne l'utilisation de l'olive noire le traitement de tumeurs de type glioblastome positif de cellules souches cancéreuses qui sont traitées par témozolomide.
PCT/TR2015/050023 2014-07-01 2015-06-30 Utilisation de l'extrait obtenu à partir de feuilles d'olive noire dans le traitement du glioblastome Ceased WO2016003383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201407670 2014-07-01
TR2014/07670 2014-07-01

Publications (1)

Publication Number Publication Date
WO2016003383A1 true WO2016003383A1 (fr) 2016-01-07

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PCT/TR2015/050023 Ceased WO2016003383A1 (fr) 2014-07-01 2015-06-30 Utilisation de l'extrait obtenu à partir de feuilles d'olive noire dans le traitement du glioblastome

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WO (1) WO2016003383A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017077134A1 (fr) * 2015-11-05 2017-05-11 Institut D'investigació Biomèdica De Girona Composés pour le traitement du cancer et/ou de la résistance au traitement du cancer par inhibition de cellules souches cancéreuses

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008273938A (ja) 2007-03-30 2008-11-13 Shiseido Co Ltd アディポネクチン産生促進剤
CN101607068A (zh) 2009-07-15 2009-12-23 中国人民解放军第四军医大学 一种治疗肝癌中药前体脂质体注射剂及其制备工艺
US20120040914A1 (en) 2010-08-11 2012-02-16 University Of North Texas Health Science Center At Fort Worth Enhancing effectiveness of glial cancer therapies
WO2013086308A1 (fr) 2011-12-09 2013-06-13 University Of Southern California Compositions et procédés pour le traitement du cancer du cerveau

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008273938A (ja) 2007-03-30 2008-11-13 Shiseido Co Ltd アディポネクチン産生促進剤
CN101607068A (zh) 2009-07-15 2009-12-23 中国人民解放军第四军医大学 一种治疗肝癌中药前体脂质体注射剂及其制备工艺
US20120040914A1 (en) 2010-08-11 2012-02-16 University Of North Texas Health Science Center At Fort Worth Enhancing effectiveness of glial cancer therapies
WO2013086308A1 (fr) 2011-12-09 2013-06-13 University Of Southern California Compositions et procédés pour le traitement du cancer du cerveau

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. OLEA: "europaea leaf extract alters microRNA expression in human glioblastoma cells", CANCER RES CLIN ONCOL., vol. 138, no. 11, 2012, pages 1831 - 44
BERRIN TUNCA ET AL: "leaf extract alters microRNA expression in human glioblastoma cells", JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, SPRINGER, BERLIN, DE, vol. 138, no. 11, 22 June 2012 (2012-06-22), pages 1831 - 1844, XP035130255, ISSN: 1432-1335, DOI: 10.1007/S00432-012-1261-8 *
GULCIN TEZCAN ET AL: "microRNA Expression Pattern Modulates Temozolomide Response in GBM Tumors with Cancer Stem Cells", CELLULAR AND MOLECULAR NEUROBIOLOGY, vol. 34, no. 5, 2 April 2014 (2014-04-02), pages 679 - 692, XP055218216, ISSN: 0272-4340, DOI: 10.1007/s10571-014-0050-0 *
HAMDI H K ET AL: "Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 334, no. 3, 2 September 2005 (2005-09-02), pages 769 - 778, XP027230048, ISSN: 0006-291X, [retrieved on 20050727], DOI: 10.1016/J.BBRC.2005.06.161 *
TEZCAN GULCIN ET AL: "Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating miRNA expression", AMERICAN JOURNAL OF CANCER RESEARCH, vol. 4, no. 5, 6 September 2014 (2014-09-06), pages 572 - 590, XP055218202, ISSN: 2156-6976 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017077134A1 (fr) * 2015-11-05 2017-05-11 Institut D'investigació Biomèdica De Girona Composés pour le traitement du cancer et/ou de la résistance au traitement du cancer par inhibition de cellules souches cancéreuses

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